Stents are currently used in a range of medical applications normally to prevent re-occlusion of a vessel after a procedure to dilate the vessel. Examples include cardiovascular, urology, and gastroenterology stents, with the former being by far the largest market. Generally, stents are made from permanent materials, such as metal alloys or non-absorbable thermoplastics, and can additionally incorporate special coatings and drugs to improve their performance in vivo. These coatings, for example, include a number of polymer coating materials for metallic stents, as well as a variety of active agents, such as agents that are anti-inflammatory or immunomodulators, antiproliferative agents, agents which affect migration and extracellular matrix production, agents which affect platelet deposition or formation of thrombis, and agents that promote vascular healing and re-endothelialization. Notably the coatings of currently marketed stents are made from permanent materials.
While the incorporation of certain active agents in coatings on the surfaces of coronary metal stents has been demonstrated to retard restenosis, it has been reported that the polymer coatings that are left after elution of the drug can present a serious risk of late thrombosis (Virmani, R et al., Coron Artery Dis. 2004;15(6):313-8). It has also been reported that the polymeric coating materials of drug-eluting stents may cause hypersensitivity reactions in the patient treated with such coated stents (Nebeker, J. R. et al., J Am Coll Cardiol 2006;47:175-81). Thus, there is a need to develop new stent coating materials that can be used to deliver drugs without the risk of late thrombosis and hypersensitivity reactions.
Furthermore, although permanent metal stents are used widely in coronary stenting applications, and their use in peripheral stenting is growing rapidly, there remain several drawbacks to the use of permanent materials to manufacture these stents (Colombo, A et al., Circulation. 2000 25;102(4):371-3, Erne, P. et al., Cardiovasc Intervent Radiol. 2005). First, metal stents are not compatible with certain methods of medical imaging, such as MRI and CT scanning systems. Second, metal stents can cause complications if the patient subsequently needs coronary artery bypass surgery, or other surgical intervention, requiring manipulation of a stented vessel. Third, the use of permanent stents can result in long-term compliance mismatches between the metal stent and the stented vessel, and fourth, in certain peripheral applications, catastrophic failure of metal stent struts has been reported.
It should also be noted that permanent stents used in urology applications to temporarily relieve obstruction in a variety of benign, malignant, and post-traumatic vessel conditions are prone to rapid encrustation (Shaw G. L. et al., Urol Res. 2005 February;33(1):17-22). Such encrustation often necessitates removal of the stent. Removal, however, requires an additional procedure, and can be difficult and painful because of tissue in-growth. The use of a degradable implant would eliminate this clinical problem.
To address the disadvantages associated with the use of permanent materials in stents and stent coatings, there have been several reports describing the use of absorbable materials to make stents and stent coatings. U.S. Pat. Nos. 5,059,211 and 5,306,286 to Stack et al. describe the use of absorbable materials to make stents. Stack, however, does not describe which specific absorbable materials a person skilled in the art would use to make an absorbable stent, or the properties necessary to make such stents.
U.S. Pat. No. 5,935,506 to Schmitz et al. describes a method to manufacture an absorbable stent from poly(3-hydroxybutyrate) ((P(3HB)).
U.S. Pat. No. 6,045,568 to Igaki et al. describes absorbable stents manufactured from knitting yarns of polylactic acid (PLA), polyglycolic acid (PGA), polyglactin (P(GA-co-LA)), polydioxanone (PDS), polyglyconate (a block co-polymer of glycolic acid and trimethylene carbonate, P(GA-co-TMC)), and a copolymer of glycolic acid or lactic acid with s-caprolactone (P(GA-co-CL) or P(LA-co-CL)).
Laaksovirta et al. describe a self-expandable, biodegradable, self-reinforced stent from P(GA-co-LA) for use in urethral applications (J Urol.2003 August;170(2 Pt 1):468-71).
The potential use of polyanhydride and polyorthoester polymers to manufacture absorbable stents has also been described by Tanguay, J. F. et al. Current Status of Biodegradable Stents, Cardiology Clinics, 12:699-713 (1994).
WO 98/51812 to Williams et al. discloses methods to remove pyrogens from polyhydroxyalkanoates, and the fabrication of stents with these depyrogenated materials. WO 99/32536 to Martin et al. and WO 00/56376 to Williams et a. disclose methods to prepare polyhydroxyalkanoates with controlled degradation rates, and the fabrication of stents with these materials.
Van der Giessen et al (Marked Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries, Circulation, 94:1690-1697 (1996)) evaluated coatings of a copolymer of glycolic acid and lactic acid (P(GA-co-LA)), polycaprolactone (PCL), poly-3-hydroxybutyrate-co-3-hydroxyvalerate (P(3HB-co-3HV), a polyorthoester, and a polyethyleneoxide-polybutylene terephthalate on metal stents, and reported that the coatings induced marked inflammatory reactions within the coronary artery.
Despite some progress towards the development of absorbable stents and stent coatings, there is currently no coronary or peripheral stent device comprising an absorbable material approved for general sale in the United States or Europe. This is partly because of the highly demanding requirements of an absorbable material used for medical stenting applications and the shortcomings of the currently available materials. Further improvements to existing materials that are considered desirable, or required, include the following elements: (i) an absorbable stent or stent coating that is biocompatible, does not create a risk of late stage thrombosis, and provides long-term vessel patency; (ii) an absorbable stent that has sufficient radial strength (or hoop strength) to prevent the collapse of the vessel wall or stent; (iii) an absorbable polymer composition that when processed into a stent or stent coating can be expanded in vivo, from a suitably low profile form to the desired diameter without surface or strut cracking or similar types of mechanical failure; (iv) an absorbable stent or permanent stent coated with an absorbable polymer that can be dilated sufficiently fast in vivo to allow deployment of the stent without risk to the patient, and using a reasonable inflation pressure if the stent is delivered using a balloon catheter; (v) an absorbable stent that does not recoil significantly after deployment; (vi) an absorbable stent that is sufficiently resistant to creep to be effective; (vii) an absorbable stent with strut thicknesses that are relatively low in profile once the stent is implanted, and with edges that are smooth; (viii) an absorbable stent coating that can be applied in a uniform manner, without defects such as web formation between struts, and a method for such application; (ix) an absorbable stent, and/or a stent coated with an absorbable material, where the struts are not susceptible to fracture after implantation, and the risk of vessel perforation is eliminated; (x) an absorbable stent that does not interfere with medical scanning systems, such as MRI and CT; (xi) an absorbable stent, and a stent coated with an absorbable material, that protects against an inflammatory response, limits smooth muscle cell proliferation, and neointimal hyperplasia after implantation, stimulates positive remodeling of the vessel wall, and eliminates long-term compliance mismatches between the stent and the vessel wall; (xii) an absorbable stent, and/or a stent coated with an absorbable material, that is sufficiently flexible to allow delivery to the desired location without strut fracture or kinking, which can conform to the shape of the affected body lumen; (xiii) an absorbable stent that contains a contrast agent, radiopaque markers, or similar material that allows the stent to be imaged using conventional scanning techniques; (xiv) an absorbable coating that adheres sufficiently strongly to a metal stent, maintains its integrity following stent expansion and does not delaminate; (xv) an absorbable stent and a coated permanent stent that can be loaded with one or more drugs or co-drugs (for example, on the inside or surface of the stent or coating) to improve the performance of the stent by controlled delivery of the drug(s), including agents that are anti-inflammatory or immunomodulators, antiproliferative agents, drugs which affect migration and extracellular matrix production, drugs which affect platelet deposition or formation of thrombis, and drugs that promote vascular healing and re-endothelialization, and that also allow larger drug loadings; (xvi) an absorbable stent and/or a stent coated with an absorbable material that can be mounted onto a catheter, and subsequently delivered in vivo without causing damage to the stent; (xvii) an absorbable stent, and an absorbable coating on a stent, that is absorbed in vivo over a time period that allows positive remodeling of the vessel wall, does not prematurely fail due to fatigue, and results in long-term vessel patency; (xviii) an absorbable stent that does not shorten in an undesirable manner upon expansion and deployment; (xix) an absorbable stent or permanent stent coated with an absorbable material that can be sterilized without detrimental loss of properties, for example, by irradiation or exposure to ethylene oxide; (xx) an absorbable stent and a coated metal stent that can be loaded with one or more drugs to improve the performance of the stent by controlled delivery of the drug(s), where the method of polymer degradation (e.g. surface erosion or bulk degradation) allows for delivery of large drugs such as proteins; (xxi) an absorbable stent and a coated permanent stent that can be loaded with one or more drugs to improve the performance of the stent by controlled delivery of the drug(s), where the low-acidity polymer degradation products (of the stent or stent coating) allows for delivery of large drugs such as proteins without drug denaturation; (xxii) an absorbable material for use in stents that has a glass transition temperature below body temperature, a melt temperature above 50° C., and a shelf-life of at least one to three years.
It is therefore an object of this invention to provide absorbable compositions that can be used to develop improved absorbable stents, and absorbable stent coatings.
It is another object of this invention to provide improved absorbable stents, and stents coated with absorbable materials.
It is a further object of this invention to provide methods for preparing improved absorbable stents and stents coated with absorbable materials.
It is a yet still further object of this invention to provide methods for the delivery of the absorbable stents and stents coated with absorbable materials.